Infant BCG vaccination is beneficial, but not sufficient
Authors: Mark Hatherill, Frank Cobelens
Journal: The Lancet Global Health (2022)

In The Lancet Global Health, Leonardo Martinez and colleagues1Martinez L Cords O Liu Q et al.Infant BCG vaccination and risk of pulmonary and extrapulmonary tuberculosis throughout the life course: a systematic review and individual participant data meta-analysis.Lancet Glob Health. 2022; 10: e1307-e1316Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar report the findings of a participant-level meta-analysis of 26 cohort studies of 68 552 individuals, all of whom lived in countries that recommend BCG vaccination at birth and were evaluated for tuberculosis for at least 6 months after household or close exposure to a person with tuberculosis. The analysis included 1782 participants who developed tuberculosis and illustrates the value of collaborative data sharing to answer important questions about infrequent disease outcomes. This meta-analysis of observational studies done within the past 20 years confirms much of what was known about the effectiveness and durability of protection offered by infant BCG vaccination from historical randomised controlled trials (RCTs).2Mangtani P Abubakar I Ariti C et al.Protection by BCG vaccine against tuberculosis: a systematic review of randomized controlled trials.Clin Infect Dis. 2014; 58: 470-480Crossref PubMed Scopus (547) Google Scholar Infant BCG vaccination was 37% effective against all forms of tuberculosis in children younger than 5 years and 42% effective against pulmonary disease in children younger than 3 years, but did not offer protection to adolescents or adults after close exposure. There should be little debate about the effectiveness of infant BCG vaccination against tuberculosis in early childhood and particularly against the most severe forms of disease, including disseminated or miliary tuberculosis and tuberculosis meningitis.2Mangtani P Abubakar I Ariti C et al.Protection by BCG vaccine against tuberculosis: a systematic review of randomized controlled trials.Clin Infect Dis. 2014; 58: 470-480Crossref PubMed Scopus (547) Google Scholar The effectiveness of BCG vaccination against all tuberculosis seems to be lower in this meta-analysis of observational studies than in historical RCTs, even among young children, which might be due to selection bias. Contacts would have been enrolled from months to years after BCG vaccination, which could have led to a cohort that did not include the most clinically vulnerable, who would had died before enrolment started. If that vulnerability was associated with poor access to BCG vaccination, the tuberculosis incidence among unvaccinated contacts could have been underestimated. Notwithstanding this possibility, the results also provide indirect support for the hypothesis that modern attenuated BCG vaccine strains might offer less protection against tuberculosis than the original strains used in early trials.3Behr MA Small PM Has BCG attenuated to impotence?.Nature. 1997; 389: 133-134Crossref PubMed Scopus (103) Google Scholar Although the meta-analysis did not show significant protection against extrapulmonary disease, it would be important to disaggregate tuberculosis meningitis from mild forms of extrapulmonary disease, such as tuberculosis lymphadenopathy. It is not possible to draw conclusions from these data about the relative contribution of BCG vaccination to protection against Mycobacterium tuberculosis infection after exposure versus progression from infection to tuberculosis disease, in part due to the composite definition of M tuberculosis infection that included both IFNγ release assay or tuberculin skin test positivity, with skin test positivity potentially being induced by BCG vaccination.4Roy A Eisenhut M Harris RJ et al.Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis.BMJ. 2014; 349g4643Crossref Scopus (342) Google Scholar However, the finding that BCG vaccination was 32% effective in children younger than 5 years with a positive IFNγ release assay or tuberculin skin test is at least consistent with protection against progression from infection to tuberculosis disease. There remains some debate about the durability of BCG vaccine-induced protection beyond childhood. The findings of Martinez and colleagues, which did not show protection against tuberculosis among children aged 5 years or older, adolescents, or adults, accord with studies showing waning effectiveness 10–15 years after infant vaccination,5Abubakar I Pimpin L Ariti C et al.Systematic review and meta-analysis of the current evidence on the duration of protection by bacillus Calmette-Guérin vaccination against tuberculosis.Health Technol Assess. 2013; 17 (v–vi.): 1-372Crossref PubMed Scopus (199) Google Scholar although notable exceptions have reported long-term protection lasting several decades.6Aronson NE Santosham M Comstock GW et al.Long-term efficacy of BCG vaccine in American Indians and Alaska Natives: a 60-year follow-up study.JAMA. 2004; 291: 2086-2091Crossref PubMed Scopus (251) Google Scholar There is also considerable debate about whether vaccinating older children, adolescents, and adults, and particularly those with previous M tuberculosis sensitisation (IFNγ release assay or tuberculin skin test positivity), with BCG offers any protection against tuberculosis;2Mangtani P Abubakar I Ariti C et al.Protection by BCG vaccine against tuberculosis: a systematic review of randomized controlled trials.Clin Infect Dis. 2014; 58: 470-480Crossref PubMed Scopus (547) Google Scholar the dataset used by Martinez and colleagues comprised individuals in settings that recommend BCG vaccination in infancy and so could not address this crucial question. Perhaps the most surprising finding from this meta-analysis is that BCG vaccination was consistently and highly protective against death (≥80% effectiveness) until 14 years of age in the four studies reporting mortality outcomes. These findings are consistent with reports of BCG vaccine-associated reductions in mortality that appeared greater than the expected reduction in mortality from the prevention of deaths caused by tuberculosis among children younger than 5 years.7Higgins JP Soares-Weiser K López-López JA et al.Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review.BMJ. 2016; 355i5170Google Scholar It is tempting to ascribe the result to the benefits of trained immunity, whereby the functional reprogramming of innate immune cells by infant BCG vaccination results in non-specific, off-target protection against other pathogens.8Kleinnijenhuis J Quintin J Preijers F et al.Long-lasting effects of BCG vaccination on both heterologous Th1/Th17 responses and innate trained immunity.J Innate Immun. 2014; 6: 152-158Crossref PubMed Scopus (351) Google Scholar BCG vaccination has been shown to protect against experimental viral infection9Arts RJW Moorlag SJCFM Novakovic B et al.BCG vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity.Cell Host Microbe. 2018; 23: 89-100.e5Summary Full Text Full Text PDF PubMed Scopus (583) Google Scholar and to reduce mortality caused by infections in infants with low birthweights,10Aaby P Roth A Ravn H et al.Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period?.J Infect Dis. 2011; 204: 245-252Crossref PubMed Scopus (390) Google Scholar but the magnitude and durability of the non-specific benefits of infant BCG vaccination remain unclear. Given the non-randomised exposure to BCG vaccination in the observational studies included in the meta-analysis and the unexpectedly large and durable mortality benefit, these data should be interpreted with caution. It is perhaps more likely that unmeasured factors associated with access, or the lack of access, to BCG vaccination in infancy contributed to long-term differences in individual mortality risk. For example, the mortality benefit might have been confounded by the HIV status of the contacts; among the 34 children younger than 15 years who died, the majority of deaths occurred in Africa in settings with a high HIV burden before the scale-up of antiretroviral treatment. The findings of this meta-analysis reinforce a consistent message for the community developing tuberculosis vaccines: infant BCG vaccination protects young children against tuberculosis, but waning effectiveness results in little or no protection against adult-type cavitary disease, which is primarily responsible for M tuberculosis transmission. A new tuberculosis vaccine strategy, one that offers either durable protection from childhood to adulthood or effective protection to adults who receive boosters, is urgently needed to impact the global tuberculosis pandemic. We declare no competing interests. Infant BCG vaccination and risk of pulmonary and extrapulmonary tuberculosis throughout the life course: a systematic review and individual participant data meta-analysisOur results suggest that BCG vaccination at birth is effective at preventing tuberculosis in young children but is ineffective in adolescents and adults. Immunoprotection therefore needs to be boosted in older populations. Full-Text PDF Open Access